Prognostic implications of volume status assessed by blood volume analysis in ambulatory heart failure.

The prognostic implications of intravascular volume status assessed by blood volume analysis (BVA) in ambulatory heart failure (HF) remain uncertain. The incremental benefits of assessing volume status, beyond the well-established filling pressures, in predicting HF outcomes are unknown.

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1-3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions-in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.

Irritable Bowel Syndrome Patient Experience: A Survey of Patient-Reported Symptoms by Irritable Bowel Syndrome Subtype and Impact on Quality of Life.

Objectives: Irritable bowel syndrome (IBS) is a chronic, debilitating, functional gastrointestinal disorder with symptoms of abdominal pain, bloating, and altered bowel behaviours of constipation (IBS-C), diarrhea (IBS-D), or a mixture of both (IBS-M). There is limited information published on the impact of symptoms on everyday life in the Canadian population. Methods: An online survey was conducted with individuals diagnosed with IBS to capture the severity and frequency of patient-reported symptoms, including impact on productivity, quality of life, healthcare utilization, treatment access, and corresponding symptom relief. Responses from the three subtypes of IBS were categorized to illustrate differences among these. Results: There were 2,470 qualified respondents (filtered from 2,981, which included nonspecific IBS). IBS-M was the most common subtype, at 44 percent. Most individuals from all three IBS subtypes reported experiencing moderate to severe abdominal pain (63-70 percent) and bloating (59-75 percent) over the previous 3 months. Persons living with IBS-C reported severe bloating (32 percent), straining (72 percent), and tenesmus (78 percent) whereas those with IBS-D experienced severe urgency (63 percent) and incontinence (29 percent). Symptoms interfered in daily life, sometimes in 46 percent and often in 23 percent of respondents. Patients reported mood and anxiety disorders as common comorbidities with IBS (mood disorders: 30-34 percent; anxiety disorders: 25-30 percent). Conclusions: This study focuses on the differences among the IBS subtypes. IBS impacts productivity and healthcare utilization, which requires further investigation on approaches to improve treatment. The frequency and severity of symptoms in IBS are high and only a few respondents reported that their symptoms are under control.

M-type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain.

The size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage-sensitive ion channels that create non-linearities in their input-output functions. Here we describe a role for the M-type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole-cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M-currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the presence of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed-firing motoneurons afforded a greater proportion of the total M-current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M-currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M-type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage-sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force. KEY POINTS: M-currents exert an inhibitory influence on spinal motor output. This inhibitory influence is exerted by controlling the recruitment, but not the firing rate, of high-threshold fast-like motoneurons, with limited influence on low-threshold slow-like motoneurons. Preferential control of fast motoneurons may be linked to a larger M-current that is activated within the subthreshold voltage range compared to slow motoneurons. Larger M-currents in fast compared to slow motoneurons are not accounted for by differences in Kv7.2 or Kv7.3 channel composition. The orderly recruitment of motoneuron subtypes is shaped by differences in the contribution of voltage-gated ion channels, including KCNQ channels. KCNQ channels may provide a target to dynamically modulate the recruitment gain across the motor pool and readily adjust movement vigour.

Patient Perspectives on Digital Interventions to Manage Heart Failure Medications: The VITAL-HF Pilot.

Use of guideline-directed medical therapy (GDMT) for treatment of heart failure with reduced ejection fraction (HFrEF) remains unacceptably low. The purpose of this study was to determine whether a digital health tool can augment GDMT for patients with HFrEF. Participants ≥ 18 years old with symptomatic HFrEF (left ventricular ejection fraction ≤ 40%) and with access to a mobile phone with internet were included. Participants were given a blood pressure cuff, instructed in its use, and given regular symptom surveys via cell-phone web-link. Data were transmitted to the Story Health web-based platform, and automated alerts were triggered based on pre-specified vital sign and laboratory data. Health coaches assisted patients with medication education, pharmacy access, and lab access through text messages and phone calls. GDMT titration plans were individually created in the digital platform by local clinicians based on entry vitals and labs. Twelve participants enrolled and completed the study. The median age and LVEF were 52.5 years (IQR, 46.5-63.5) and 25% (IQR, 22.5-35.5), respectively. There were 10 GDMT initiations, 52 up-titrations, and 13 down-titrations. Five participants engaged in focus-group interviews following study completion to understand first-hand perspectives regarding the use of digital tools to manage GDMT. Participants expressed comfort knowing that there were clinicians regularly reviewing their data. This alleviated concerns of uncertainty in daily living, led to an increased feeling of security, and empowered patients to understand decision-making regarding GDMT. Frequent medication changes, and the associated financial impact, were common concerns. Remote titration of GDMT for HFrEF is feasible and appears to be a patient-centered approach to care.

Splanchnic Nerve Modulation Effects on Surrogate Measures of Venous Capacitance.

Background Splanchnic nerve modulation (SNM) is an emerging procedure to reduce cardiac filling pressures in heart failure. Although the main contributor to reduction in cardiac preload is thought to be increased venous capacitance in the splanchnic circulation, supporting evidence is limited. We examined changes in venous capacitance surrogates pre- and post-SNM. Methods and Results This is a prespecified analysis of a prospective, open-label, single-arm interventional study evaluating the effects of percutaneous SNM with ropivacaine in chronic heart failure with elevated filling pressures at rest and with exercise. Patients underwent cardiopulmonary exercise testing with invasive hemodynamic assessment pre- and post-SNM. Blood pressure changes with modified Valsalva maneuver and hemoconcentration, pre- and post-SNM were compared using a repeated measures model. Inferior vena cava diameter and collapsibility (>50% decrease in size with inspiration), and presence of bendopnea pre- and post-SNM were also compared. Fifteen patients undergoing SNM (age 58 years, 47% women, 93% with left ventricular ejection fraction ≤35%) were included. After SNM, changes in systolic blood pressure during Valsalva (peak-to-trough) were greater (41 versus 48 mm Hg, P=0.025). Exercise-induced hemoconcentration was unchanged (0.63 versus 0.43 g/dL, P=0.115). Inferior vena cava diameter was reduced (1.59 versus 1.30 cm, P=0.034) with higher collapsibility (33% versus 73%, P=0.014). Bendopnea was less (47% versus 13%, P=0.025). Conclusions SNM resulted in increased venous capacitance, associated decreased cardiac preload, and decreased bendopnea. Minimally invasive measures of venous capacitance could serve as markers of successful SNM. Long-term effects of SNM on venous capacitance warrant further investigation for heart failure management. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03453151.

Per- and polyfluoroalkyl substances (PFAS) in United States tapwater: Comparison of underserved private-well and public-supply exposures and associated health implications.

Drinking-water quality is a rising concern in the United States (US), emphasizing the need to broadly assess exposures and potential health effects at the point-of-use. Drinking-water exposures to per- and poly-fluoroalkyl substances (PFAS) are a national concern, however, there is limited information on PFAS in residential tapwater at the point-of-use, especially from private-wells. We conducted a national reconnaissance to compare human PFAS exposures in unregulated private-well and regulated public-supply tapwater. Tapwater from 716 locations (269 private-wells; 447 public supply) across the US was collected during 2016-2021 including three locations where temporal sampling was conducted. Concentrations of PFAS were assessed by three laboratories and compared with land-use and potential-source metrics to explore drivers of contamination. The number of individual PFAS observed ranged from 1 to 9 (median: 2) with corresponding cumulative concentrations (sum of detected PFAS) ranging from 0.348 to 346 ng/L. Seventeen PFAS were observed at least once with PFBS, PFHxS and PFOA observed most frequently in approximately 15% of the samples. Across the US, PFAS profiles and estimated median cumulative concentrations were similar among private wells and public-supply tapwater. We estimate that at least one PFAS could be detected in about 45% of US drinking-water samples. These detection probabilities varied spatially with limited temporal variation in concentrations/numbers of PFAS detected. Benchmark screening approaches indicated potential human exposure risk was dominated by PFOA and PFOS, when detected. Potential source and land-use information was related to cumulative PFAS concentrations, and the number of PFAS detected; however, corresponding relations with specific PFAS were limited likely due to low detection frequencies and higher detection limits. Information generated supports the need for further assessments of cumulative health risks of PFAS as a class and in combination with other co-occurring contaminants, particularly in unmonitored private-wells where information is limited or not available.

What to know about 2.0: Revisions to the pediatric emergency medicine milestones.

Introduction: The Accreditation Council for Graduate Medical Education (ACGME) adopted educational milestones for trainee assessment in 2013, as a key component of the Next Accreditation System. Two years later, the ACGME, American Board of Pediatrics (ABP), and American Board of Emergency Medicine (ABEM) collaborated to create specialty-specific subcompetencies in pediatric emergency medicine (PEM). Since that time, emerging data have demonstrated the need to revise specialty milestones. Consequently, the ACGME summoned a working group to revise the original PEM milestones. Methods: The PEM Milestones 2.0 Working Group convened in April 2021, comprising diverse representation from ACGME staff, PEM and EM attendings, PEM fellowship program directors, PEM fellows, and community members, overseen by the ACGME's vice president for milestones development. The group met virtually six times over 3 months, with concurrent independent and subgroup work, to draft the PEM Milestones 2.0 and supplemental guide. Results: The working group's revisions generated concise descriptions of behavioral anchors to define skill acquisition more accurately; attention to the transition from residency to fellowship training; incorporation of harmonized milestones for non-patient care and non-medical knowledge domains; and increased emphasis on diversity, equity, and inclusion. A supplemental guide was also designed to aid programs in designing programmatic assessment related to specialty-specific milestones. Conclusions: The PEM Milestones 2.0 provide an updated, specialty-specific framework to guide the development and assessment of PEM fellows and training programs. Future work may focus on faculty and learner development, advancing validity evidence, strengthening content expertise, and integrating milestones with specialty-specific entrustable professional activities.

Inappropriate Shock Delivery Is Common During Pediatric In-Hospital Cardiac Arrest.

OBJECTIVES: To characterize inappropriate shock delivery during pediatric in-hospital cardiac arrest (IHCA). DESIGN: Retrospective cohort study. SETTING: An international pediatric cardiac arrest quality improvement collaborative Pediatric Resuscitation Quality [pediRES-Q]. PATIENTS: All IHCA events from 2015 to 2020 from the pediRES-Q Collaborative for which shock and electrocardiogram waveform data were available. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 418 shocks delivered during 159 cardiac arrest events, with 381 shocks during 158 events at 28 sites remaining after excluding undecipherable rhythms. We classified shocks as: 1) appropriate (ventricular fibrillation [VF] or wide complex ≥ 150/min); 2) indeterminate (narrow complex ≥ 150/min or wide complex 100-149/min); or 3) inappropriate (asystole, sinus, narrow complex < 150/min, or wide complex < 100/min) based on the rhythm immediately preceding shock delivery. Of delivered shocks, 57% were delivered appropriately for VF or wide complex rhythms with a rate greater than or equal to 150/min. Thirteen percent were classified as indeterminate. Thirty percent were delivered inappropriately for asystole (6.8%), sinus (3.1%), narrow complex less than 150/min (11%), or wide complex less than 100/min (8.9%) rhythms. Eighty-eight percent of all shocks were delivered in ICUs or emergency departments, and 30% of those were delivered inappropriately. CONCLUSIONS: The rate of inappropriate shock delivery for pediatric IHCA in this international cohort is at least 30%, with 23% delivered to an organized electrical rhythm, identifying opportunity for improvement in rhythm identification training.

A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain.

The mammalian brain is composed of millions to billions of cells that are organized into numerous cell types with specific spatial distribution patterns and structural and functional properties. An essential step towards understanding brain function is to obtain a parts list, i.e., a catalog of cell types, of the brain. Here, we report a comprehensive and high-resolution transcriptomic and spatial cell type atlas for the whole adult mouse brain. The cell type atlas was created based on the combination of two single-cell-level, whole-brain-scale datasets: a single-cell RNA-sequencing (scRNA-seq) dataset of ~7 million cells profiled, and a spatially resolved transcriptomic dataset of ~4.3 million cells using MERFISH. The atlas is hierarchically organized into five nested levels of classification: 7 divisions, 32 classes, 306 subclasses, 1,045 supertypes and 5,200 clusters. We systematically analyzed the neuronal, non-neuronal, and immature neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell type organization in different brain regions, in particular, a dichotomy between the dorsal and ventral parts of the brain: the dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. We also systematically characterized cell-type specific expression of neurotransmitters, neuropeptides, and transcription factors. The study uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types across the brain, suggesting they mediate a myriad of modes of intercellular communications. Finally, we found that transcription factors are major determinants of cell type classification in the adult mouse brain and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole-mouse-brain transcriptomic and spatial cell type atlas establishes a benchmark reference atlas and a foundational resource for deep and integrative investigations of cell type and circuit function, development, and evolution of the mammalian brain.

Agreements, Behaviour, and Change: Sex Outside the Relationship in Male HIV-negative Partners in HIV Serodiscordant Relationships in Australia, Brazil, and Thailand.

Male HIV serodiscordant couples have diverse relationship agreements regarding sex outside the relationship. We examined the relationship agreements as described by 343 male HIV-negative partners in HIV serodiscordant relationships in Australia, Brazil and Thailand participating in a multi-year cohort study. At baseline, 125 (34.1%) HIV-negative partners reported no agreement, 115 (33.5%) had a monogamous agreement, and 103 (37.9%) had an open agreement allowing sex outside the relationship. Relationship agreements were largely stable over time, with 76% of HIV-negative men reporting the same agreement across follow up, while changes were predominantly towards having an open agreement. Behaviour largely matched relationship agreements, and the predictors of breaking an agreement by having condomless anal intercourse (CLAI) with an outside partner were CLAI within the relationship (OR = 3.17, 95%CI: 1.64-6.14, p < 0.001) and PrEP use in the last three months (OR = 3.42, 95%CI: 1.48-7.92, p = 0.004). When considering HIV transmission risk for HIV-negative men in serodiscordant relationships, greater focus needs to be placed on sex that is occurring outside the relationship and the agreements that facilitate this.

Contaminant Exposure and Transport from Three Potential Reuse Waters within a Single Watershed.

Global demand for safe and sustainable water supplies necessitates a better understanding of contaminant exposures in potential reuse waters. In this study, we compared exposures and load contributions to surface water from the discharge of three reuse waters (wastewater effluent, urban stormwater, and agricultural runoff). Results document substantial and varying organic-chemical contribution to surface water from effluent discharges (e.g., disinfection byproducts [DBP], prescription pharmaceuticals, industrial/household chemicals), urban stormwater (e.g., polycyclic aromatic hydrocarbons, pesticides, nonprescription pharmaceuticals), and agricultural runoff (e.g., pesticides). Excluding DBPs, episodic storm-event organic concentrations and loads from urban stormwater were comparable to and often exceeded those of daily wastewater-effluent discharges. We also assessed if wastewater-effluent irrigation to corn resulted in measurable effects on organic-chemical concentrations in rain-induced agricultural runoff and harvested feedstock. Overall, the target-organic load of 491 g from wastewater-effluent irrigation to the study corn field during the 2019 growing season did not produce substantial dissolved organic-contaminant contributions in subsequent rain-induced runoff events. Out of the 140 detected organics in source wastewater-effluent irrigation, only imidacloprid and estrone had concentrations that resulted in observable differences between rain-induced agricultural runoff from the effluent-irrigated and nonirrigated corn fields. Analyses of pharmaceuticals and per-/polyfluoroalkyl substances in at-harvest corn-plant samples detected two prescription antibiotics, norfloxacin and ciprofloxacin, at concentrations of 36 and 70 ng/g, respectively, in effluent-irrigated corn-plant samples; no contaminants were detected in noneffluent irrigated corn-plant samples.

Juxtaposition of intensive agriculture, vulnerable aquifers, and mixed chemical/microbial exposures in private-well tapwater in northeast Iowa.

In the United States and globally, contaminant exposure in unregulated private-well point-of-use tapwater (TW) is a recognized public-health data gap and an obstacle to both risk-management and homeowner decision making. To help address the lack of data on broad contaminant exposures in private-well TW from hydrologically-vulnerable (alluvial, karst) aquifers in agriculturally-intensive landscapes, samples were collected in 2018-2019 from 47 northeast Iowa farms and analyzed for 35 inorganics, 437 unique organics, 5 in vitro bioassays, and 11 microbial assays. Twenty-six inorganics and 51 organics, dominated by pesticides and related transformation products (35 herbicide-, 5 insecticide-, and 2 fungicide-related), were observed in TW. Heterotrophic bacteria detections were near ubiquitous (94 % of the samples), with detection of total coliform bacteria in 28 % of the samples and growth on at least one putative-pathogen selective media across all TW samples. Health-based hazard index screening levels were exceeded frequently in private-well TW and attributed primarily to inorganics (nitrate, uranium). Results support incorporation of residential treatment systems to protect against contaminant exposure and the need for increased monitoring of rural private-well homes. Continued assessment of unmonitored and unregulated private-supply TW is needed to model contaminant exposures and human-health risks.

Commercial volumetric MRI reporting tools in multiple sclerosis: a systematic review of the evidence.

PURPOSE: MRI is integral to the diagnosis of multiple sclerosis (MS) and is important for clinical prognostication. Quantitative volumetric reporting tools (QReports) can improve the accuracy and objectivity of MRI-based assessments. Several QReports are commercially available; however, validation can be difficult to establish and does not currently follow a common pathway. To aid evidence-based clinical decision-making, we performed a systematic review of commercial QReports for use in MS including technical details and published reports of validation and in-use evaluation. METHODS: We categorized studies into three types of testing: technical validation, for example, comparison to manual segmentation, clinical validation by clinicians or interpretation of results alongside clinician-rated variables, and in-use evaluation, such as health economic assessment. RESULTS: We identified 10 companies, which provide MS lesion and brain segmentation and volume quantification, and 38 relevant publications. Tools received regulatory approval between 2006 and 2020, contextualize results to normative reference populations, ranging from 620 to 8000 subjects, and require T1- and T2-FLAIR-weighted input sequences for longitudinal assessment of whole-brain volume and lesions. In MS, six QReports provided evidence of technical validation, four companies have conducted clinical validation by correlating results with clinical variables, only one has tested their QReport by clinician end-users, and one has performed a simulated in-use socioeconomic evaluation. CONCLUSION: We conclude that there is limited evidence in the literature regarding clinical validation and in-use evaluation of commercial MS QReports with a particular lack of clinician end-user testing. Our systematic review provides clinicians and institutions with the available evidence when considering adopting a quantitative reporting tool for MS.

Bottled water contaminant exposures and potential human effects.

BACKGROUND: Bottled water (BW) consumption in the United States and globally has increased amidst heightened concern about environmental contaminant exposures and health risks in drinking water supplies, despite a paucity of directly comparable, environmentally-relevant contaminant exposure data for BW. This study provides insight into exposures and cumulative risks to human health from inorganic/organic/microbial contaminants in BW. METHODS: BW from 30 total domestic US (23) and imported (7) sources, including purified tapwater (7) and spring water (23), were analyzed for 3 field parameters, 53 inorganics, 465 organics, 14 microbial metrics, and in vitro estrogen receptor (ER) bioactivity. Health-benchmark-weighted cumulative hazard indices and ratios of organic-contaminant in vitro exposure-activity cutoffs were assessed for detected regulated and unregulated inorganic and organic contaminants. RESULTS: 48 inorganics and 45 organics were detected in sampled BW. No enforceable chemical quality standards were exceeded, but several inorganic and organic contaminants with maximum contaminant level goal(s) (MCLG) of zero (no known safe level of exposure to vulnerable sub-populations) were detected. Among these, arsenic, lead, and uranium were detected in 67 %, 17 %, and 57 % of BW, respectively, almost exclusively in spring-sourced samples not treated by advanced filtration. Organic MCLG exceedances included frequent detections of disinfection byproducts (DBP) in tapwater-sourced BW and sporadic detections of DBP and volatile organic chemicals in BW sourced from tapwater and springs. Precautionary health-based screening levels were exceeded frequently and attributed primarily to DBP in tapwater-sourced BW and co-occurring inorganic and organic contaminants in spring-sourced BW. CONCLUSION: The results indicate that simultaneous exposures to multiple drinking-water contaminants of potential human-health concern are common in BW. Improved understandings of human exposures based on more environmentally realistic and directly comparable point-of-use exposure characterizations, like this BW study, are essential to public health because drinking water is a biological necessity and, consequently, a high-vulnerability vector for human contaminant exposures.

Heat shock protein amplification improves cerebellar myelination in the Npc1nih mouse model.

BACKGROUND: Niemann-Pick disease type C (NPC) is a rare prematurely fatal lysosomal lipid storage disease with limited therapeutic options. The prominent neuropathological hallmarks include hypomyelination and cerebellar atrophy. We previously demonstrated the efficacy of recombinant human heat shock protein 70 (rhHSP70) in preclinical models of the disease. It reduced glycosphingolipid levels in the central nervous system (CNS), improving cerebellar myelination and improved behavioural phenotypes in Npc1nih (Npc1-/-) mice. Furthermore, treatment with arimoclomol, a well-characterised HSP amplifier, attenuated lysosomal storage in NPC patient fibroblasts and improved neurological symptoms in Npc1-/- mice. Taken together, these findings prompted the investigation of the effects of HSP amplification on CNS myelination. METHODS: We administered bimoclomol daily or rhHSP70 6 times per week to Npc1-/- (BALB/cNctr-Npc1m1N/J, also named Npc1nih) mice by intraperitoneal injection from P7 through P34 to investigate the impact on CNS myelination. The Src-kinase inhibitor saracatinib was administered with/without bimoclomol twice daily to explore the contribution of Fyn kinase to bimoclomol's effects. FINDINGS: Treatment with either bimoclomol or rhHSP70 improved myelination and increased the numbers of mature oligodendrocytes (OLs) as well as the ratio of active-to-inactive forms of phosphorylated Fyn kinase in the cerebellum of Npc1-/- mice. Additionally, treatment with bimoclomol preserved cerebellar weight, an effect that was abrogated when co-administered with saracatinib, an inhibitor of Fyn kinase. Bimoclomol-treated mice also exhibited increased numbers of immature OLs within the cortex. INTERPRETATION: These data increase our understanding of the mechanisms by which HSP70 regulates myelination and provide further support for the clinical development of HSP-amplifying therapies in the treatment of NPC. FUNDING: Funding for this study was provided by Orphazyme A/S (Copenhagen, Denmark) and a Pathfinder Award from The Wellcome Trust.

Tapwater Exposures, Effects Potential, and Residential Risk Management in Northern Plains Nations.

In the United States (US), private-supply tapwater (TW) is rarely monitored. This data gap undermines individual/community risk-management decision-making, leading to an increased probability of unrecognized contaminant exposures in rural and remote locations that rely on private wells. We assessed point-of-use (POU) TW in three northern plains Tribal Nations, where ongoing TW arsenic (As) interventions include expansion of small community water systems and POU adsorptive-media treatment for Strong Heart Water Study participants. Samples from 34 private-well and 22 public-supply sites were analyzed for 476 organics, 34 inorganics, and 3 in vitro bioactivities. 63 organics and 30 inorganics were detected. Arsenic, uranium (U), and lead (Pb) were detected in 54%, 43%, and 20% of samples, respectively. Concentrations equivalent to public-supply maximum contaminant level(s) (MCL) were exceeded only in untreated private-well samples (As 47%, U 3%). Precautionary health-based screening levels were exceeded frequently, due to inorganics in private supplies and chlorine-based disinfection byproducts in public supplies. The results indicate that simultaneous exposures to co-occurring TW contaminants are common, warranting consideration of expanded source, point-of-entry, or POU treatment(s). This study illustrates the importance of increased monitoring of private-well TW, employing a broad, environmentally informative analytical scope, to reduce the risks of unrecognized contaminant exposures.